1. Field of the Invention
The present invention is generally directed toward antifungal compositions and methods of treating fungal infections with the same. Particularly, the antifungal composition comprises, as an active ingredient, one or more bicyclic sesquiterpene compounds, and specifically drimane derivatives. The antifungal composition can be formulated to include one or more pharmaceutically acceptable carriers for the sesquiterpene compound(s). The composition can also be administered to animals and humans through various means, such as topically, in the treatment of pathogenic fungal infections.
2. Description of the Prior Art
Fungi have emerged in the last two decades as major causes of human disease costing the U.S. health care system between $3-5 billion annually. As people are using immunosuppressive and antimicrobial chemotherapies increasingly, various types of fungal infections including superficial and life threatening invasive infections, are on the rise. C. albicans is a major fungal pathogen affecting all ages and the fourth leading cause of nosocomial bloodstream infections in the U.S. C. albicans and other Candida spp. cause mucosal, disseminated and invasive candidiasis, especially among patients who are immune-compromised or hospitalized with serious underlying diseases. The overall mortality for invasive diseases caused by Candida spp. and Aspergillus spp. is around 50% despite new diagnostic and therapeutic strategies. While there are more than 150 species of Candida, about 15 species are recognized as frequent human pathogens including: C. albicans, C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis. Among these, C. albicans is by far the most common species isolated from humans and is a frequent denizen of the oropharynx, mucosal surfaces, gastrointestinal and genitourinary tracts.
Other fungal pathogens such as Cryptococcus and Aspergillus spp. also contribute significant morbidity and mortality. In the developing world, there are ˜1 million cases of cryptococcal disease per year, resulting in 675 000 deaths (Park, et. al. AIDS 2009, 23, 525-530). Cryp. neoformans is an opportunistic fungal pathogen that causes meningitis in immune-compromised individuals. Often found in soils contaminated with bird feces, C. neoformans enters its host through the lungs via inhalation of spores. Some of the cryptococcal species are hypervirulent and have recently drawn considerable public attention due to their causative role in the cryptococcosis outbreak throughout the Pacific Northwest.
Aspergillus spp. are ubiquitous molds found widely in the environment as saprophytes and produce microscopic spores or conidia which upon inhalation, cause invasive pulmonary disease. In immune-compromised patients such as those undergoing hematopoietic stem cell transplantation, solid organ transplantation, or receiving chemotherapeutic agents or immunomodulator agents, invasive aspergillosis remains the most important cause of infection-related mortality. Among several species of Aspergillus, A. fumigatus and A. flavus are frequent pathogens.
Dermatophytes are another group of keratinophilic pathogenic fungi that cause a variety of infections in humans and animals. Some of these fungi include Trichophyton tonsurans (scalp ringworm), T. equinum, and Microporum gypseum (gardener's ringworm). Emerging fungal disease such as zygomycosis is life-threatening particularly during the aftermath of natural calamities (e.g., tsunamis, hurricanes, and tornados).
Allergic fungal syndromes are increasingly recognized. There are increasing reports of dermatophytes and rare molds (e. g. Bipolaris, Fusarium and Curvularia) that cause devastating infections in a range of patients (Denning and Hope, Trends Micro. 2010, 18, 195-204).
Because fungi are eukaryotes, the development of antifungal therapeutics that are non-toxic to humans is challenging. In the last 30 years, only one new class of antifungal compounds (β-glucan synthase inhibitor, the echinocandins) has been introduced into clinical practice. Although this drug is an important addition, it has a number of limitations including ineffectiveness against Cryptococcus sp. and poor oral bioavailability. Other currently available antimycotics contain similar limitations with respect to efficacy against certain fungi, bioavailability, and the development of antifungal resistance by fungal pathogens.